The provision of HIV antiretroviral (ARV) therapy in Africa will have beneficial health and social effects, but will present many challenges. Since the drugs are now being initiated in Uganda, we have a narrow window of opportunity to assess the population-level impact of ARVs on HIV transmission and epidemiology, on behaviors in both HIV+ and HIV uninfected persons, and on sociodemographic indicators. Information is also needed on the emergence and transmission of drug resistance mutations, the effects of prior maternal nevirapine use on subsequent ARV effectiveness, and on barriers to ARV acceptance and adherence. The Rakai Health Sciences Program has received PEPFAR funds to initiate an ARV program in rural Rakai District, Uganda. Since 1994, we have conducted the Rakai Community Cohort Study (RCCS) and have longitudinal population-based information on HIV epidemiology, and on community risk behaviors, health and sociodemographic characteristics. These data provide a baseline for the assessment of ARV effects. Rakai has a mature, generalized epidemic, with a prevalence of 15% and an incidence of approximately 1.4/100 py. Under the proposed R01 (complementary to PEPFAR), we plan to conduct integrated quantitative and qualitative research in RCCS communities (n= 12,000 adults and approximately 600 children) and in non-RCCS comparison communities (n = 1,000 adults). We propose to examine epidemiological effects of ARVs (HIV incidence and prevalence; emergence and transmission of drug-resistant HIV, treatment acceptance and effectiveness, mother-to-child HIV transmission by subtype [A, D, AD recombinant]; as well as behavioral, social and demographic effects (behavioral disinhibition, use of HIV counseling and testing, use of other prevention services, contraceptive use, mortality, fertility, marital stability and orphanhood). We will also examine knowledge and attitudes towards ARVs, and the effects of stigma on ARV use. The study will provide unique data to guide HIV care in Africa and for projecting the course of the epidemic in the ARV era.